The goal of this research project is to define the structure and radioactive label for ligands that will permit quantitative measurement of serotonin transporter (5-HTT) sites in living brain by external imaging with positron (PET) or single photon (SPECT) emission tomography. The serotonin transporter is known to play a role in several physiological and pathophysiological processes, especially in depression, anxiety, seasonal affective disorder, bulimia, and psychosis, as demonstrated by post-mortem and preliminary imaging studies. A radiotracer that bound specifically to 5-HTT would be of great utility in diagnosis, monitoring treatment, and research of such disorders. However, there is not yet a suitable tracer that allows quantitation in areas of the brain with low densities of 5-HTT, such as the cortex. Based on preliminary in vitro binding results using a classical structure-activity relationship approach, we found that certain 4'-biphenyl analogs of phenyltropanes showed nanomolar affinity to 5-HTT and >50-fold selectivity with respect to other monoamine transporters. In this application we propose to test the following hypotheses: 1) derivatives with pi-donor substituents on the 4'-position of 4-phenyl piperidine will favor binding to 5-HTT relative to dopamine transporter (DAT) and norepinephrine transporter (NET); and 2) elimination of the C6-C7 bridge of the tropane (to yield piperidine analogs) will reduce the lipophilicity of our compounds and have lower nonspecific binding than the corresponding tropane or nor-tropane compound.